Novel form of (r)-n-[5-methyl-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydro-2-naphthyl]-4-morpholinobenzamide

ABSTRACT

This invention relates to a novel form of a serotonin h5-HT 1B -receptor antagonist, namely a novel form of a salt of (R)-N-[5-methyl-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydro-2-naphtyl]-4-morpholinobenzamide referred to as (R)-N-[5-methyl-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydro-2-naphtyl]-4-morpholinobenzamide monohydrobromide Form A. The invention also relates to processes for preparation of said of Form A, which form has a potential use after suitable pharmaceutical formulation in medical treatment, preferably in CNS disorders, over active bladder or vasospam, or growth control of tumors.

FIELD OF THE INVENTION

[0001] This invention relates to a novel form of a serotoninh5-HT_(1B)-receptor antagonist, namely a novel form of a salt of(R)-N-[5-methyl-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydro-2-naphtyl]-4-morpholinobenzamidereferred to as(R)-N-[5-methyl-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydro-2-naphtyl]-4-morpholinobenzamidemonohydrobromide Form A. The invention also relates to processes forproduction of said Form A, which form has a potential use after suitablepharmaceutical formulation in medical treatment.

PRIOR ART

[0002][5-Methyl-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydro-2-naphtyl]-4-morpholinobenzamide,both the (R)- and (S)-enantiomer and the racemate and their methods ofpreparation are disclosed in WO 99/05134.

BACKGROUND OF THE INVENTION

[0003] Various central nervous system disorders such as depression,anxiety, etc. appear to involve the disturbance of the neurotransmittersnoradrenaline (NA) and/or 5-hydroxytryptamine(5-HT), the latter alsoknown as serotonin. The drugs most frequently used in the treatment ofdepression are believed to act by improving the neurotransmission ofeither or both of these physiological agonists. It appears that theenhancement of 5-HT neurotransmission primarily affects the depressedmood and anxiety, whereas the enhancement of noradrenalineneurotransmission affects the retardation symptoms occurring indepressed patients.

[0004] Serotonin, or 5-HT, activity is thought to be involved in manydifferent types of psychiatric disorders. For instance it is thoughtthat an increase in 5-HT activity is associated with anxiety, while adecrease in 5-HT release has been associated with depression. Serotoninhas in addition been implicated in such diverse conditions as eatingdisorders, gastrointestinal disorders, cardiovascular regulation andsexual behaviour.

[0005] The compoundN-[5-methyl-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydro-2-naphtyl]-4-morpholinobenzamide(both enantiomers as well as the racemate) has an extremely lowsolubility in water and a slow release rate which rate is pH dependent,i.e. the rate is different in the stomach and the intestines. From apharmaceutical formulation point of view it is very difficult todissolve the base rapidly enough and maintain the same dissolved in thegastric juice until a sufficient amount of substance has been absorbed.

DISCLOSURE OF THE INVENTION

[0006] The object of the invention is a novel form of a salt of(R)-N-[5-methyl-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydro-2-naphtyl]-4-morpholinobenzamide,namely(R)-N-[5-methyl-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydro-2-naphtyl]-4-morpholinobenzamidemonohydrobromide Form A, which is a specific crystal modification of(R)-N-[5-methyl-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydro-2-naphtyl]-4-morpholinobenzamidemonohydrobromide.

[0007] Another object of the invention is a process which reproduciblygives(R)-N-[5-methyl-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydro-2-naphtyl]-4-morpholinobenzamidemonohydrobromide Form A. In addition it has been shown that(R)-N-[5-methyl-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydro-2-naphtyl]-4-morpholinobenzamidemonohydrobromide can crystallize in other crystalline forms, for exampleForm B.

[0008](R)-N-[5-methyl-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydro-2-naphtyl]-4-morpholinobenzamidemonohydrobromide Form A is a crystal modification form of(R)-N-[5-methyl-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydro-2-naphtyl]-4-morpholinobenzamidemonohydrobromide, which has several advantageous properties:

[0009] it has a satisfactory solubility in water;

[0010] it has a satisfactory thermal stability;

[0011] it is non-hygroscopic;

[0012] it has a good stability against light exposure.

[0013] It is predicted that these advantageous properties will lead tosatisfactory chemical stability and long shelf life both for the puresubstance and for pharmaceutical dosage forms containing(R)-N-[5-methyl-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydro-2-naphtyl]-4-morpholinobenzamidemonohydrobromide Form A. Consequently, there may be fewer demands onpackages, in particular on the water permeability and lighttransmission. Packages can thus be made of materials that are lesscomplicated and more environmentally friendly, for instance blisterpacks can be made of transparent material so that the tablets can bevisible and the total package is smaller than in the case of aluminiumblister packs.

Characteristics of(R)-N-[5-methyl-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydro-2-naphtyl]-4-morpholinobenzamidemonohydrobromide Form A

[0014] The novel form of a salt of(R)-N-[5-methyl-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydro-2-naphtyl]-4-morpholinobenzamideof the invention, i.e.(R)-N-[5-methyl-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydro-2-naphtyl]-4-morpholinobenzamidemonohydrobromide Form A, can be distinguished from other forms bymethods such as Powder X-ray diffractometry (XRPD).

DETAILED DESCRIPTION OF THE INVENTION

[0015] In a first aspect, the invention thus provides(R)-N-[5-methyl-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydro-2-naphtyl]-4-morpholinobenzamidemonohydrobromide Form A, preferably substantially crystallographicallypure(R)-N-[5-methyl-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydro-2-naphtyl]-4-morpholinobenzamidemonohydrobromide Form A. A crystallographically pure form is a crystalmodification that, as far as can be judged from XRPD measurements,contains no peaks from other crystal modifications. The term“substantially crystallographically pure(R)-N-[5-methyl-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydro-2-naphtyl]-4-morpholinobenzamidemonohydrobromide Form A” should thus be understood as(R)-N-[5-methyl-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydro-2-naphtyl]-4-morpholinobenzamidemonohydrobromide Form A containing only small amounts of any othercrystalline form of(R)-N-[5-methyl-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydro-2-naphtyl]-4-morpholinobenzamidemonohydrobromide; preferably not more than 10% and most preferably notmore than 3%, of any other crystalline form of(R)-N-[5-methyl-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydro-2-naphtyl]-4-morpholinobenzamidemonohydrobromide. The term “form” is in this context equivalent to theterm “crystal modification”.

[0016](R)-N-[5-methyl-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydro-2-naphtyl]-4-morpholinobenzamidemonohydrobromide Form A can be characterized by the X-ray powderdiffraction pattern: Form A d-value Relative d-value Relative d-valueRelative (Å) intensity (Å) intensity (Å) intensity 11.7 vs 4.24 vw 3.09w 10.9 s 4.16 vw 3.03 w 8.0 w 4.10 s 2.97 w 7.4 m 3.99 w 2.90 m 7.1 w3.96 m 2.87 w 6.3 w 3.92 vs 2.82 vw 6.2 s 3.89 m 2.79 vw 5.9 s 3.83 m2.74 w 5.8 vw 3.80 s 2.71 w 5.6 m 3.71 m 2.66 w 5.5 vw 3.67 m 2.64 vw5.4 m 3.65 m 2.61 vw 5.3 vs 3.61 vw 2.58 vw 5.1 vw 3.57 vw 2.53 vw 5.1 m3.54 w 2.48 vw 4.95 vs 3.50 m 2.41 vw 4.82 s 3.45 s 2.39 vw 4.71 w 3.39m 2.38 vw 4.60 s 3.31 s 2.36 vw 4.56 vs 3.21 m 2.34 vw 4.45 vs 3.17 m2.28 vw 4.28 vw 3.11 m 2.27 vw

Preparation of(R)-N-[5-methyl-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydro-2-naphtyl]-4-morpholinobenzamidemonohydrobromide Form A

[0017] In a further aspect, the invention relates to a process for thepreparation of(R)-N-[5-methyl-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydro-2-naphtyl]-4-morpholinobenzamidemonohydrobromide Form A.(R)-N-[5-methyl-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydro-2-naphtyl]-4-morpholinobenzamidemonohydrobromide Form A may be prepared under controlled conditions froma mixture of one or more organic solvents. It is preferred to use amixture of organic solvents, which is miscible with water. The optimalratio of organic solvents in the mixture to obtain(R)-N-[5-methyl-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydro-2-naphtyl]-4-morpholinobenzamidemonohydrobromide Form A is strongly dependent on the characteristics ofthe chosen organic solvents and the process conditions e.g. thetemperature, the pressure and the solubility of(R)-N-[5-methyl-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydro-2-naphtyl]-4-morpholinobenzamidemonohydrobromide in each of the solvents, as well as in the mixture ofthe solvents and their content of water.

[0018] In particular,(R)-N-[5-methyl-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydro-2-naphtyl]-4-morpholinobenzamidemonohydrobromide Form A may be prepared by:

[0019] (i) partly dissolving any non-A form of(R)-N-[5-methyl-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydro-2-naphtyl]-4-morpholinobenzamidemonohydrobromide in organic solvent(s) optionally containing a minoramount of water and stirring until Form A is formed, or by

[0020] (ii) reaction crystallizing(R)-N-[5-methyl-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydro-2-naphtyl]-4-morpholinobenzamideor a salt different from(R)-N-[5-methyl-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydro-2-naphtyl]-4-morpholinobenzamidemonohydrobromide with a buffering acidic salt of hydrobromic acid inorganic solvent(s) optionally containing a minor amount of water; or by

[0021] (iii) crystallizing from a solution of(R)-N-[5-methyl-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydro-2-naphtyl]-4-morpholinobenzamidemonohydrobromide in a mixture of organic solvent(s) and water wherebycrystals of(R)-N-[5-methyl-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydro-2-naphtyl]-4-morpholinobenzamidemonohydrobromide Form A are formed spontaneously; or when crystals arenot formed spontaneously, followed by 1) cooling the mixture; 2)evaporating some of the solvent or 3) mixing with a precipitatingsolvent whereby crystals of(R)-N-[5-methyl-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydro-2-naphtyl]-4-morpholinobenzamidemonohydrobromide Form A are formed.

[0022] Method (i) is a transformation of polymorphs in slurry. Any non-Aform of(R)-N-[5-methyl-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydro-2-naphtyl]-4-morpholinobenzamidemonohydrobromide, e.g. amorphous material or for instance(R)-N-[5-methyl-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydro-2-naphtyl]-4-morpholinobenzamidemonohydrobromide Form B, is initially partly dissolved in organicsolvent(s) optionally containing a minor amount of water and stirreduntil the desired Form A is formed. The process comprises atransformation in the slurry without a complete dissolution of thestarting material. Such transformation may occur, as it is known in theart, when there exists a form with higher thermodynamic stability thanat the prevailing conditions. The driving force for the process is thenormally lower solubility of the more stable form.

[0023] Method (ii) is a reaction crystallization in organic solvent(s)optionally containing a minor amount of water, with a buffering acidicsalt of hydrobromic acid, preferably an amine salt of hydrobromic acidhaving a pK_(A) of 3-7.5, and most preferably imidazole hydrobromide.The starting material is e.g.(R)-N-[5-methyl-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydro-2-naphtyl]-4-morpholinobenzamideor a salt different from(R)-N-[5-methyl-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydro-2-naphtyl]-4-morpholinobenzamidemonohydrobromide. The composition of the resulting mixture afteraddition of the reactant should be such that it contains the ratio oforganic solvent(s) optionally containing a minor amount of waterrequired for formation of(R)-N-[5-methyl-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydro-2-naphtyl]-4-morpholinobenzamidemonohydrobromide Form A. The crystallization may start spontaneously,but it is preferable to add seeds of(R)-N-[5-methyl-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydro-2-naphtyl]-4-morpholinobenzamidemonohydrobromide Form A.

[0024] Method (iii) is a crystallization from a solution of(R)-N-[5-methyl-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydro-2-naphtyl]-4-morpholinobenzamidemonohydrobromide in a mixture of organic solvent(s) and water. Thestarting solution of(R)-N-[5-methyl-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydro-2-naphtyl]-4-morpholinobenzamidemonohydrobromide might have been formed either by dissolution of alreadyisolated(R)-N-[5-methyl-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydro-2-naphtyl]-4-morpholinobenzamidemonohydrobromide, or might have been formed in a previous process stepwhere(R)-N-[5-methyl-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydro-2-naphtyl]-4-morpholinobenzamidemonohydrobromide has been formed by a chemical reaction. The solutionmay become supersaturated with respect to(R)-N-[5-methyl-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydro-2-naphtyl]-4-morpholinobenzamidemonohydrobromide Form A due to the lower solubility of this form andcrystallization of(R)-N-[5-methyl-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydro-2-naphtyl]-4-morpholinobenzamidemonohydrobromide Form A can therefore occur spontaneously. However, ifthe original solution is undersaturated with respect to(R)-N-[5-methyl-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydro-2-naphtyl]-4-morpholinobenzamidemonohydrobromide Form A, crystallization may be induced by decreasingthe solubility of(R)-N-[5-methyl-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydro-2-naphtyl]-4-morpholinobenzamidemonohydrobromide Form A in the system e.g. by cooling the mixture, byevaporating some of the solvents or by mixing with, e.g. by adding, someprecipitating solvent. The water content in the final mixture iscritical, but adjustment to the required solvent/water ratio can be doneat any time in the process, e.g. before or during mixing with aprecipitating solvent.

[0025] When the starting material for the crystallization of(R)-N-[5-methyl-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydro-2-naphtyl]-4-morpholinobenzamidemonohydrobromide is an already isolated(R)-N-[5-methyl-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydro-2-naphtyl]-4-morpholinobenzamidemonohydrobromide (for instance amorphous material or Form B), theprocess can be described in more detail as follows:

[0026](R)-N-[5-methyl-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydro-2-naphtyl]-4-morpholinobenzamidemonohydrobromide is dissolved in one or more organic solvents,preferably polar organic solvents, most preferably ethanol. In order todissolve the starting material completely, it may be helpful to warm upthe solvents or to add a small amount of water to the solvent system.The preferred amount of solvent mixture is 2-20 ml/g of(R)-N-[5-methyl-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydro-2-naphtyl]-4-morpholinobenzamidemonohydrobromide, most preferably 3-15 ml/g. It is preferable that thetotal mixture is agitated, e.g. stirred, during dissolution. Water maybe added before or during mixing with a precipitating solvent. It ispreferable to add all the required water before mixing with theprecipitating solvent, the ratio of water to organic solvent prior toaddition of precipitating solvent in the resulting solvent system beingfrom 1:1000 to 1:2, preferably 1:1000 to 1:20, depending on the organicsolvents.

[0027] The crystallization of(R)-N-[5-methyl-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydro-2-naphtyl]-4-morpholinobenzamidemonohydrobromide Form A may be obtained by mixing with a specificprecipitating solvent at a temperature up to the boiling point of thespecific solvent mixture. It is preferred that the temperature of themixture during mixing with the precipitating solvent is 0 to +80° C.,most preferably +20° C. to +75° C., and for the precipitating solventpreferably to be at ambient temperature before mixing. It is preferredto add the precipitating solvent to the(R)-N-[5-methyl-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydro-2-naphtyl]-4-morpholinobenzamidemonohydrobromide solution. The precipitation solvent may be addedcontinuously or discontinuously, preferably continuously over a periodof up to 12 hours. As the precipitating solvent, an organic solvent maybe used, preferably a nonpolar solvent, e.g. acetone, ethyl methylketone, isobutyl methyl ketone, methyl acetate, ethyl acetate, isopropylacetate, most preferably ethyl acetate. The amount of precipitatingsolvent should be such that the concentration of(R)-N-[5-methyl-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydro-2-naphtyl]-4-morpholinobenzamidemonohydrobromide in the resulting mixture is higher than the solubility.The preferred ratio of precipitating solvent to the(R)-N-[5-methyl8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydro-2-naphtyl]-4-morpholinobenzamidemonohydrobromide solution should be in the range of 1:1 to 10:1 byvolume. The water content in the final mixture should preferably bebelow 5% by volume or otherwise the yield will be unacceptably low orthe desired(R)-N-[5-methyl-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydro-2-naphtyl]-4-morpholinobenzamidemonohydrobromide Form A may not be formed.

[0028] The crystallization may start spontaneously but it has frequentlybeen found desirable to add seeds of(R)-N-[5-methyl-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydro-2-naphtyl]-4-morpholinobenzamidemonohydrobromide Form A after the first addition of the precipitatingsolvent to induce crystallization and to obtain a higher crystallizationrate and thus a shorter process time. Mixing, e.g. agitation, ispreferable both during mixing of the precipitating solvent and the(R)-N-[5-methyl-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydro-2-naphtyl]-4-morpholinobenzamidemonohydrobromide solution and during the crystallization process. Thecrystallization should continue for a period to ensure thatcrystallization is as complete as possible, e.g. 1 to 30 hours,preferably 5 to 12 hours.

[0029] The(R)-N-[5-methyl-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydro-2-naphtyl]-4-morpholinobenzamidemonohydrobromide Form A crystals may be separated from the solution,e.g. by filtration or centrifugation, followed by washing with a washingliquid, preferably a solvent mixture in which(R)-N-[5-methyl-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydro-2-naphtyl]-4-morpholinobenzamidemonohydrobromide Form A has a very low solubility, most preferably theprecipitating solvent. The preferred ratio of washing liquid to theamount of product is 1:1 to 10:1 by weight. It is preferable to cool theslurry to below room temperature before separation of the crystals. Theseparated(R)-N-[5-methyl-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydro-2-naphtyl]-4-morpholinobenzamidemonohydrobromide Form A crystals should be dried to constant weight,e.g. at +30° C. to +60° C., preferably at reduced pressure, for, e.g. 10to 120 hours. The product from the precipitation process may comprisecrystalline rods, needles or agglomerates or a mixture of rods, needlesand agglomerates of(R)-N-[5-methyl-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydro-2-naphtyl]-4-morpholinobenzamidemonohydrobromide Form A.

[0030] The above disclosed methods for preparation of(R)-N-[5-methyl-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydro-2-naphtyl]-4-morpholinobenzamidemonohydrobromide Form A are reproducible and give a substantially pureand crystalline substance. The process of crystallization of(R)-N-[5-methyl-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydro-2-naphtyl]-4-morpholinobenzamidemonohydrobromide Form A fulfils pharmaceutical criteria andspecifications and may reduce batch to batch variability of drug in e.g.crystallinity. Filtration and drying conditions are favourable for(R)-N-[5-methyl-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydro-2-naphtyl]-4-morpholinobenzamidemonohydrobromide Form A.

[0031] In a further aspect, the invention provides a compound obtainableby a process as described above, or, in a broader sense,(R)-N-[5-methyl-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydro-2-naphtyl]-4-morpholinobenzamidemonohydrobromide Form A comprising such a compound.

Medical Use of(R)-N-[5-methyl-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydro-2-naphtyl]-4-morpholinobenzamidemonohydrobromide Form A

[0032] In a further aspect the present invention provides the use of(R)-N-[5-methyl-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydro-2-naphtyl]-4-morpholinobenzamidemonohydrobromide Form A in therapy as a h5-HT_(1B) antagonist or partialagonist for the treatment or prevention of disorders in the centralnervous system (CNS), e.g. in the treatment or prevention of5-hydroxytryptamine mediated disorders and medical disturbances. It canfor example be used in mood disorders, especially episodes of majordepression, dysthymia, seasonal affective disorder, depressive phases ofbipolar disorder, anxiety disorders such as obsessive compulsivedisorder, panic disorder with/without agoraphobia, social phobia,specific phobia, generalized anxiety disorder, posttraumatic stressdisorder, disorders of impulse control, e.g. trichotellomania,personality disorders, sleep disorders, eating disorders, e.g. obesity,anorexia, bulimia, premenstrual syndrome including premenstrualdysphoric disorder, sexual disturbances, abuse and/or dependencedisorders, e.g. alcoholism, nicotine, autism, attention deficitdisorder, hyperactivity disorder, migraine, memory disorders, e.g. ageassociated memory impairment, presenile and senile dementia such asAlzheimer's disease, vascular dementia, pathological aggression,schizophrenia, endocrine disorders, e.g. hyperprolactinaemia, stroke,dyskinesia, Parkinson's disease, disorders of thermoregulation, pain,hypertension, over active bladder such as over active bladder, urinaryincontinence, detrusor instability, neurogenic bladder, detrusorhyperreflexia, nocturnal enurisis, e.g, bed-wetting, in children,urinary frequency, urinary urgency, urge incontinence, stressincontinence, mixed incontinence, unstable bladder secondary toprostatitis or interstitial cystitis, vasospasm and growth control oftumors, e.g. lung carcinoma.

[0033] Pharmaceutical Formulations

[0034] In another aspect, the invention relates to pharmaceuticalcompositions comprising(R)-N-[5-methyl-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydro-2-naphtyl]-4-morpholinobenzamidemonohydrobromide Form A as active ingredient optionally in associationwith diluents, excipients or inert carriers.

[0035](R)-N-[5-methyl-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydro-2-naphtyl]-4-morpholinobenzamidemonohydrobromide Form A may be formulated for administration in aconvenient way and the invention includes all pharmaceuticalcompositions comprising this particular crystal form adapted for use inhuman medicine. Oral administration is preferable but other types ofadministration such as rectal or parenteral (dermal, nasal, tracheal,bronchial, or via inhalation route) administration are of interest.

[0036] Examples of formulations are tablets, capsules, pellets,granules, suspensions, solutions and suppositories, which formulationscan have immediate-release or modified-release properties. Thepharmaceutical compositions are prepared by techniques, which are knownper se. Preferably, each daily dose of the active ingredient in anamount of 1 mg to 400 mg, and may be administered 1 to 4 times per day.

EXAMPLES OF THE INVENTION Example 1 Preparation of(R)-N-[5-methyl-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydro-2-naphtyl]-4-morpholinobenzamidemonohydrobromide Form A from(R)-N-[5-methyl-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydro-2-naphtyl]-4-morpholinobenzamideby Reaction Crystallisation:

[0037] To a slurry of(R)-N-[5-methyl-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydro-2-naphtyl]-4-morpholinobenzamidein ethanol (493 g, 1.1 mole, 2.5 L) is added a mixture of imidazole (82g, 1.2 mole) and HBr in acetic acid (33 w/w %, 124 g, 1.5 mole) inethanol (2.5 L) at 65° C. After the addition of all the material isdissolved, the solution is filtered clear and then heated at 80° C. for2 h. The reaction mixture is then cooled to 65° C. and seeding crystalsof(R)-N-[5-methyl-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydro-2-naphtyl]-4-morpholinobenzamidemonohydrobromide Form A are added. From 65° C. a cooling profile isstarted with a cooling rate of 7-8° C./h until the temperature is −10°C. The slurry is then stirred for 8 hrs at −10° C. before the crystalsare filtered off and washed with cool ethanol. Drying under vacuum (50°C.) gives 533 g (92%) of(R)-N-[5-methyl-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydro-2-naphtyl]-4-morpholinobenzamidemonohydrobromide Form A;

[0038]¹H NMR (300 MHz, DMSO-d₆) δ8.24 (d, J=7.5 Hz, 1 H), 7.86 (d, J=8Hz, 2 H), 6.92-7.08 (m, 1 H), 7.01 (d, J=7.5 Hz, 1 H), 6.98 (d, J=8 Hz,1 H), 6.86 (d, J=8 Hz, 1 H), 3.61-4.07 (m, 5 H), 2.42-3.61 (m, 16 H),2.84 (s, 3 H), 2.00-2.20 (m, 1 H), 2.15 (s, 3 H), 1.63-1.88 (m, 1 H).For further characterization, see below.

Example 2 Preparation of(R)-N-[5-methyl-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydro-2-naphtyl]-4-morpholinobenzamidemonohydrobromide Form A by transformation in a slurry:

[0039] Crude(R)-N-[5-methyl-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydro-2-naphtyl]-4-morpholinobenzamidemonohydrobromide (10.9 kg, 20.6 moles) is stirred in isopropanol (IPA,80 L) at 60° C. for 19 hrs and then cooled to room temperature beforefiltration. Drying under vacuum at 50° C. gives 10.8 kg (99% yield) ofpure(R)-N-[5-methyl-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydro-2-naphtyl]-4-morpholinobenzamidemonohydrobromide Form A.

Example 3 Preparation of(R)-N-[5-methyl-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydro-2-naphtyl]-4-morpholinobenzamidemonohydrobromide Form A by recrystallization of crude(R)-N-[5-methyl-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydro-2-naphtyl]-4-morpholinobenzamidemonohydrobromide:

[0040] To crude(R)-N-[5-methyl-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydro-2-naphtyl]-4-morpholinobenzamidemonohydrobromide (98 g, 0.22 mole) is added ethanol (0.57 L) and water(28.5 ml) at room temperature and a slurry is obtained. The slurry isthen heated to 80° C. at which all solids are dissolved. The solution isthen cooled to 70° C. before slowly adding ethyl acetate (0.25 L) to thesolution. Seeding crystals of(R)-N-[5-methyl-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydro-2-naphtyl]-4-morpholinobenzamidemonohydrobromide Form A are added followed by the addition of ethylacetate (1.15 L) and the solution is cooled to −10° C. over 6 h. Theslurry is stirred at −10° C. for 5 h before the crystals are filteredoff. Drying under vacuum at 50° C. gives 88 g of pure(R)-N-[5-methyl-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydro-2-naphtyl]-4-morpholinobenzamidemonohydrobromide Form A.

Example of a Method for Generating Another Crystal Modification Form of(R)-N-[5-methyl-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydro-2-naphtyl-4-morpholinobenzamidemonohydrobromide Preparation of(R)-N-[5-methyl-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydro-2-naphtyl]-4-morpholinobenzamidemonohydrobromide Form B from crude(R)-N-[5-methyl-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydro-2-naphtyl]-4-morpholinobenzamidemonohydrobromide:

[0041] To crude(R)-N-[5-methyl-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydro-2-naphtyl]-4-morpholinobenzamidemonohydrobromide (0.8 g, 1.5 mmole) is added ethanol (18 ml) andeverything is dissolves at 70° C. The solution is then cooled to 5° C.and stirred at 5° C. for 2.5 hrs. The crystals are filtered off anddried at 40° C. under vacuum. This gives 0.7 g(R)-N-[5-methyl-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydro-2-naphtyl]-4-morpholinobenzamidemonohydrobromide Form B.

Characterisation of(R)-N-[5-methyl-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydro-2-naphtyl]-4-morpholinobenzamidemonohydrobromide Forms A and B

[0042] X-ray Powder Diffraction (XRPD)

[0043] X-ray diffraction analysis was performed according to standardmethods, which can be found in e.g. Kitaigorodsky, A. I. (1973),Molecular Crystals and Molecules, Academic Press, New York; Bunn C. W.(1948), Chemical Crystallography, Clarendon Press, London; or Klug, H.P. & Alexander, L. E. (1974), X-ray Diffraction Procedures, John Wiley &Sons, New York.

[0044] The X-ray powder diffraction (XRPD) patterns of(R)-N-[5-methyl-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydro-2-naphtyl]-4-morpholinobenzamidemonohydrobromide Forms A and B, obtained in Bragg-Brentano geometry, areshown in FIGS. 1 and 2.

[0045] The d-values and relative intensities are shown in Table 1. Bothforms are highly crystalline as judged from the XRPD diffractograms.

[0046] Table 1.

[0047] X-ray powder diffraction d-values and relative intensities,calculated as obtained with fixed slits, for(R)-N-[5-methyl-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydro-2-naphtyl]-4-morpholinobenzamidemonohydrobromide Forms A and B. Relative intensities are defined as verystrong (vs) above 50% relative intensity, as strong (s) between 25-50%,as medium (m) between 10-25%, as weak (w) between 5-10% and as very weak(vw) up to 5%. Form A Form B d-value Relative d-value Relative (Å)intensity (Å) intensity 11.7 vs 14.7 vw 10.9 s 8.9 vs 8.0 w 7.9 vw 7.4 m7.3 m 7.1 w 6.6 m 6.3 w 6.2 vs 6.2 s 5.9 w 5.9 s 5.8 s 5.8 vw 5.6 vs 5.6m 4.97 m 5.5 vw 4.87 s 5.4 m 4.68 w 5.3 vs 4.64 w 5.1 vw 4.44 s 5.1 m4.41 s 4.95 vs 4.37 m 4.82 s 4.33 m 4.71 w 4.24 w 4.60 s 4.19 m 4.56 vs4.09 m 4.45 vs 3.96 vs 4.28 vw 3.89 w 4.24 vw 3.82 s 4.16 vw 3.77 s 4.10s 3.65 w 3.99 w 3.56 s 3.96 m 3.50 w 3.92 vs 3.48 m 3.89 m 3.43 w 3.83 m3.38 m 3.80 s 3.32 w 3.71 m 3.26 w 3.67 m 3.22 m 3.65 m 3.12 w 3.61 vw3.09 w 3.57 vw 3.04 w 3.54 w 3.02 vw 3.50 m 2.97 w 3.45 s 2.93 w 3.39 m2.86 w 3.31 s 2.77 vw 3.21 m 2.65 vw 3.17 m 2.55 vw 3.11 m 2.49 vw 3.09w 2.41 vw 3.03 w 2.37 vw 2.97 w 2.34 w 2.90 m 2.31 vw 2.87 w 2.82 vw2.79 vw 2.74 w 2.71 w 2.66 w 2.64 vw 2.61 vw 2.58 vw 2.53 vw 2.48 vw2.41 vw 2.39 vw 2.38 vw 2.36 vw 2.34 vw 2.28 vw 2.27 vw

[0048] The XRPD-data for(R)-N-[5-methyl-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydro-2-naphtyl]-4-morpholinobenzamidemonohydrobromide Form A may be fitted to a primitive orthorhombic unitcell with cell dimensions

[0049] a=21,88 Å

[0050] b=23,37 Å

[0051] c=10,13 Å

[0052] The space group, as determined from systematic absences isP2₁2₁2₁. The volume of the unit cell is 5180 Å³.

[0053] The XRPD-data may for(R)-N-[5-methyl-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydro-2-naphtyl]-4-morpholinobenzamidemonohydrobromide Form B (monohydrate) may be fitted to a primitiveorthorhombic unit cell with cell dimensions

[0054] a=9,89 Å

[0055] b=29,23 Å

[0056] c=9,40 Å

[0057] The volume of the unit cell is 2720 Å³.

[0058](R)-N-[5-methyl-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydro-2-naphtyl]-4-morpholinobenzamidemonohydrobromide Form A was found to be an anhydrate by thermalgravimetric analysis (TGA). Furthermore, it does not sorb essentialamounts of water as measured by dynamic vapour sorption (DVS), 0,8% at80% RH and 25° C.

[0059](R)-N-[5-methyl-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydro-2-naphtyl]-4-morpholinobenzamidemonohydrobromide Form B was found to be a monohydrate using acombination of TGA and DVS analysis. Karl Fischer titration verifies thepresence of water. Although form B can desorb water when dried, leadingto another crystal modification, it readily resorbs water again givingform B back.

[0060] Stability

[0061] The stability of[5-Methyl-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydro-2-naphtyl]-4-morpholinobenzamide(=“Base”in tables below) and(R)-N-[5-methyl-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydro-2-naphtyl]-4-morpholinobenzamidemonohydrobromide Form A (=“Form A” in tables below), as bulk drugsubstance and in solutions at different pH levels after exposure todaylight and at elevated temperatures, has been studied.

[0062] Result Summary

[0063] The results for the stability of drug substance are presented inTable 2. The bulk substances are very stable, both in daylight and at90° C. There are no significant differences between the HPLC purity of[5-Methyl-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydro-2-naphtyl]-4-morpholinobenzamide(=Base) and(R)-N-[5-methyl-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydro-2-naphtyl]-4-morpholinobenzamidemonohydrobromide Form A (=Form A) at the tested conditions.

[0064] Three solutions were made from each batch of drug substance. Onesolution in pure water, one in 0.1 mM HCl (pH 4.1) and one in 0.1 M HCl(pH 1.1). The content of[5-Methyl-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydro-2-naphtyl]-4-morpholinobenzamide(=Base) was determined by HPLC, all results are calculated as the base.The results are presented in Tables 3-5 below.

[0065] The stability at pH 1.1 and pH 4.1 is good and equal for both[5-Methyl-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydro-2-naphtyl]-4-morpholinobenzamide(=Base) and(R)-N-[5-methyl-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydro-2-naphtyl]-4-morpholinobenzamidemonohydrobromide Form A (=Form A), except at 60° C. where the Base isless stable than Form A (more pronounced at pH 4.1 than at pH 1.1).

[0066] In the pure water solutions (pH was not adjusted), the Base isless stable than Form A at room temperature. The 60° C. condition is theonly case where the salt is less stable than the Base.

[0067] The conclusion is that from a chemical stability point of view(R)-N-[5-methyl-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydro-2-naphtyl]-4-morpholinobenzamidemonohydrobromide Form A (=Form A) is more stable or equal to[5-Methyl-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydro-2-naphtyl]-4-morpholinobenzamide(=Base) in all solutions tested (except for the water solution at 60°C.). The bulk stability towards temperature and daylight are equal forboth[5-Methyl-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydro-2-naphtyl]-4-morpholinobenzamide(=Base) and(R)-N-[5-methyl-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydro-2-naphtyl]-4-morpholinobenzamidemonohydrobromide Form A (=Form A). TABLE 2 Stability of drug substanceHPLC Purity (100% - related substances). RT is room temperature. BaseForm A Base Form A Time daylight, RT daylight, RT 90° C. 90° C. Start 100%  99.7%  100%  99.7%  2 days n. a n. a.  99.9%  99.6%  8 days 99.9%  99.6%  99.9%  99.6% 14 days  99.9%  99.5%  99.9%  99.5% 21 days 99.9%  99.5%  99.9%  99.6% 30 days  99.9%  99.5%  99.9%  99.4%

[0068] TABLE 3 Stability in water solutions, assay, all values are mgbase/ml. Base Form A daylight daylight, Base Form A Base Form A BaseForm A Time RT RT Dark RT Dark RT 60° C. 60° C. 5° C. 5° C. Start0.00698 0.0248 0.00698 0.0248 0.00698 0.0248 0.00698 0.0248 (100%)(100%) (100%) (100%) (100%) (100%) (100%) (100%)  2 days n.a n.a n.a n.a105%  84% n.a n.a  8 days  95% 100%  94%  99% 104%  81% 101% 101% 14days  94% 101%  94%  99% 106%  76% 101% 100% 23 days  91% 100%  95%  97%102%  82% 102%  99%

[0069] TABLE 4 Solution in 0.1 mM HCl, pH 4.1, assay, all values are mgbase/ml Base Form A daylight daylight, Base Form A Base Form A Base FormA Time RT RT Dark RT Dark RT 60° C. 60° C. 5° C. 5° C. Start 0.04430.0490 0.0443 0.0490 0.0443 0.0490 0.0443 0.0490 (100%) (100%) (100%)(100%) (100%) (100%) (100%) (100%)  2 days n.a n.a n.a n.a  96%  97% n.an.a  8 days n.a n.a  99%  99%  93%  93% 100% 100% 14 days  98%  99%  98% 99%  67%  90%  99% 100% 23 days  98%  97%  97%  98%  57%  81%  99% 100%

[0070] TABLE 5 Solution in 0.1 M HCl, pH 1.1, assay, all values are mgbase/ml Base Form A daylight daylight, Base Form A Base Form A Base FormA Time RT RT Dark RT Dark RT 60° C. 60° C. 5° C. 5° C. Start 0.479 0.5040.479 0.504 0.479 0.504 0.479 0.504 (100%) (100%) (100%) (100%) (100%)(100%) (100%) (100%)  2 days n.a n.a n.a n.a  98% 100% n.a n.a  8 daysn.a n.a 100% 101%  96%  97%  99% 100% 14 days 100% 100% 100%  99%  91% 95% 100% 100% 23 days  98%  98%  98%  98%  83%  88%  97%  98%

[0071] Solubility in Water

[0072] The solubility in water for(R)-N-[5-methyl-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydro-2-naphtyl]-4-morpholinobenzamidemonohydrobromide Form A was determined to be 6.4 mg/mL as the free baseby HPLC-analysis, which is satisfactory for pharmaceutical formulations.The solubility for(R)-N-[5-methyl-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydro-2-naphtyl]-4-morpholinobenzamideis 0.034 mg/mL under the same conditions.

[0073] Conclusions

[0074] The solid state characterization shows that(R)-N-[5-methyl-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydro-2-naphtyl]-4-morpholinobenzamidemonohydrobromide Form A is crystalline, non-hygroscopic and has asatisfactory solubility in water. The chemical stability of drugsubstance as bulk and in solutions at different pH levels after exposureto daylight and at elevated temperatures, has been studied. From theseexperiments it can be concluded that(R)-N-[5-methyl-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydro-2-naphtyl]-4-morpholinobenzamidemonohydrobromide Form A has at least the same stability as(R)-N-[5-methyl-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydro-2-naphtyl]-4-morpholinobenzamidewith the exception of water solutions at 60° C.

1.(R)-N-[5-methyl-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydro-2-naphtyl]-4-morpholinobenzamidemonohydrobromide Form A. 2.(R)-N-[5-methyl-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydro-2-naphtyl]-4-morpholinobenzamidemonohydrobromide Form A according to claim 1 which is substantiallycrystallographically pure(R)-N-[5-methyl-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydro-2-naphtyl]-4-morpholinobenzamidemonohydrobromide Form A. 3.(R)-N-[5-methyl-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydro-2-naphtyl]-4-morpholinobenzamidemonohydrobromide Form A according to claim 2 containing not more than10% of any other crystalline form(R)-N-[5-methyl-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydro-2-naphtyl]-4-morpholinobenzamidemonohydrobromide. 4.(R)-N-[5-methyl-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydro-2-naphtyl]-4-morpholinobenzamidemonohydrobromide Form A according to claim 1, providing an X-ray powderdiffraction pattern exhibiting substantially the following d-values andrelative intensities: Form A d-value Relative d-value Relative d-valueRelative (Å) intensity (Å) intensity (Å) intensity 11.7 vs 4.24 vw 3.09w 10.9 s 4.16 vw 3.03 w 8.0 w 4.10 s 2.97 w 7.4 m 3.99 w 2.90 m 7.1 w3.96 m 2.87 w 6.3 w 3.92 vs 2.82 vw 6.2 s 3.89 m 2.79 vw 5.9 s 3.83 m2.74 w 5.8 vw 3.80 s 2.71 w 5.6 m 3.71 m 2.66 w 5.5 vw 3.67 m 2.64 vw5.4 m 3.65 m 2.61 vw 5.3 vs 3.61 vw 2.58 vw 5.1 vw 3.57 vw 2.53 vw 5.1 m3.54 w 2.48 vw 4.95 vs 3.50 m 2.41 vw 4.82 s 3.45 s 2.39 vw 4.71 w 3.39m 2.38 vw 4.60 s 3.31 s 2.36 vw 4.56 vs 3.21 m 2.34 vw 4.45 vs 3.17 m2.28 vw 4.28 vw 3.11 m 2.27 vw


5. A process for the preparation of(R)-N-[5-methyl-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydro-2-naphtyl]-4-morpholinobenzamidemonohydrobromide Form A according to claim 1, characterized by (i)partly dissolving any non-Form A of(R)-N-[5-methyl-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydro-2-naphtyl]-4-morpholinobenzamidemonohydrobromide in organic solvent(s) optionally containing a minoramount of water and stirring until Form A is formed, or by (ii) reactioncrystallizing(R)-N-[5-methyl-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydro-2-naphtyl]-4-morpholinobenzamideor a salt different from(R)-N-[5-methyl-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydro-2-naphtyl]-4-morpholinobenzamidemonohydrobromide with a buffering acidic salt of hydrobromic acid inorganic solvent(s) optionally containing a minor amount of water; or by(iii) crystallizing from a solution of(R)-N-[5-methyl-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydro-2-naphtyl]-4-morpholinobenzamidemonohydrobromide in a mixture of organic solvent(s) and water wherebycrystals of(R)-N-[5-methyl-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydro-2-naphtyl]-4-morpholinobenzamidemonohydrobromide Form A are formed spontaneously; or when crystals arenot formed spontaneously, followed by 1) cooling the mixture, 2)evaporating some of the solvent or 3) mixing with a precipitatingsolvent whereby crystals of (R)-N-[5-methyl-8-(4-methylpiperazin1-yl)-1,2,3,4-tetrahydro-2-naphtyl]-4-morpholinobenzamidemonohydrobromide Form A are formed.
 6. A process according to claim 5wherein in i) the non-A-form of(R)-N-[5-methyl-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydro-2-naphtyl]-4-morpholinobenzamidemonohydrobromide is an amorphous material or(R)-N-[5-methyl-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydro-2-naphtyl]-4-morpholinobenzamidemonohydrobromide Form B.
 7. A process according to claim 5 wherein inii) the buffering acidic salt of hydrobromic acid is an amine salt ofhydrobromic acid having a pK_(A) of 3-7.5.
 8. A process according toclaim 5 wherein in ii) the buffering acidic salt of hydrobromic acid isimidazole hydrobromide.
 9. A process according to claim 5 wherein iniii) the(R)-N-[5-methyl-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydro-2-naphtyl]-4-morpholinobenzamidemonohydrobromide has been formed either by dissolution of alreadyisolated(R)-N-[5-methyl-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydro-2-naphtyl]-4-morpholinobenzamidemonohydrobromide, or has been formed in a previous process step where(R)-N-[5-methyl-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydro-2-naphtyl]-4-morpholinobenzamidemonohydrobromide has been formed by a chemical reaction.
 10. Apharmaceutical formulation comprising as active ingredient atherapeutically effective amount of(R)-N-[5-methyl-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydro-2-naphtyl]-4-morpholinobenzamidemonohydrobromide Form A as defined in any one of claims 1-4 optionallyin association with diluents, excipients or inert carriers.
 11. Apharmaceutical formulation according to claim 10 for the treatment of5-hydroxytryptamine mediated disorders.
 12. A pharmaceutical formulationaccording to claim 11 for use in the treatment of disorders in thecentral nervous system and/or over active bladder or vasospasm; or forgrowth control of tumors.
 13. A pharmaceutical formulation according toclaim 12 for use in the treatment of mood disorders, anxiety disorders,personality disorders, obesity, anorexia, bulimia, pre-menstrualsyndrome, sexual disturbances, alcoholism, tobacco abuse, autism,attention deficit, hyperactivity disorder, migraine, memory disorders,pathological aggression, schizophrenia, endocrine disorders, stroke,dyskinesia, Parkinson's disease, thermoregulatory disorders, pain orhypertension.
 14. The use of a(R)-N-[5-methyl-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydro-2-naphtyl]-4-morpholinobenzamidemonohydrobromide Form A defined in any of claims 1-4 in the manufactureof a medicament for the treatment of 5-hydroxytryptamine mediateddisorders.
 15. The use of a(R)-N-[5-methyl-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydro-2-naphtyl]-4-morpholinobenzamidemonohydrobromide Form A defined in any of claims 1-4 in the manufactureof a medicament for the treatment of disorders in the central nervoussystem and/or over active bladder or vasospasm; or for growth control oftumors.
 16. The use according to claim 14 in the manufacture of amedicament for the treatment of mood disorders, anxiety disorders,personality disorders, obesity, anorexia, bulimia, pre-menstrualsyndrome, sexual disturbances, alcoholism, tobacco abuse, autism,attention deficit, hyperactivity disorder, migraine, memory disorders,pathological aggression, schizophrenia, endocrine disorders, stroke,dyskinesia, Parkinson's disease, thermoregulatory disorders, pain orhypertension.
 17. A method of treatment of 5-hydroxytryptamine mediateddisorders which comprises administration of a therapeutically effectiveamount of(R)-N-[5-methyl-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydro2-naphtyl]-4-morpholinobenzamidemonohydrobromide Form A as defined in any of claims 1-4, to a patientsuffering from 5-hydroxytryptamine mediated disorders.
 18. A method forthe treatment of disorders in the central nervous system and/or overactive bladder or vasospasm or for growth control of tumors byadministering to a mammal including man in need of such a treatment atherapeutically effective amount of(R)-N-[5-methyl-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydro-2-naphtyl]-4-morpholinobenzamidemonohydrobromide Form A as defined in any of claims 1-4.
 19. A methodaccording to claim 17 for the treatment of mood disorders, anxietydisorders, personality disorders, obesity, anorexia, bulimia,pre-menstrual syndrome, sexual disturbances, alcoholism, tobacco abuse,autism, attention deficit, hyperactivity disorder, migraine, memorydisorders, pathological aggression, schizophrenia, endocrine disorders,stroke, dyskinesia, Parkinson's disease, thermoregulatory disorders,pain or hypertension.